What Is HLH?

HLH stands for hemophagocytic lymphohistiocytosis. HLH is a life-threatening condition. It is often caused by an inherited problem of the immune system, which is called “primary” HLH or “familial” HLH.

In patients with primary HLH, cells of the immune system, principally T cells and NK cells, don’t work properly to destroy infected or damaged cells as they should. Because of this, the immune system becomes overstimulated and over activated. The immune system then begins to damage the patient’s own tissues and organs, including the bone marrow, the liver and the brain.

Doctors can even sometimes see cells of the immune system “eating” other cells when they look at the bone marrow from a patient. This is called hemophagocytosis.

Some patients are diagnosed with what is called “secondary” HLH. This term is used when your doctor thinks your HLH may have occurred for a variety of different reasons, but not necessarily because of an inherited condition associated with abnormal function of the immune system.

HLH can be challenging to diagnose because the initial symptoms may mimic common infections. Symptoms of HLH may include:

Persistent fevers

Rash

Enlarged liver

Enlarged spleen

Enlarged lymph nodes

Anemia

Low platelets

Low white blood cells

Jaundice

Hepatitis

Liver failure

Respiratory issues (coughing, respiratory distress)

Seizures

Altered mental functions

HLH can only be diagnosed with the proper blood tests. Blood tests may include looking at blood cell counts, liver function numbers, and markers of immune system activation such as ferritin and soluble IL-2 receptor levels. A sample of bone marrow may be obtained to look for hemophagocytosis. Doctors may collect some fluid from the spinal canal to look for HLH affecting the brain.

X-rays, CT scans, ultrasounds or MRIs may be performed. Your doctor may also perform testing to look for infections that can be associated with HLH.

Primary / familial HLH is caused by problems in genes that control how the immune system kills virus-infected or other abnormal cells in a person’s body. These genes include PRF1, MUNC 13-4, STXBP2 and STX11. XIAP / BIRC4 mutations can also be considered as a cause of familial HLH.

HLH also occurs in some closely related diseases. These include X-linked lymphoproliferative disease (XLP), which is due to mutations in the SH2D1A gene (XLP1) or XIAP / BIRC4 gene (XLP2), Griscelli syndrome type II, which is due to mutations in the Rab27a gene, and Chediak-Higashi syndrome, which is due to mutations in the LYST gene.

The T cells and NK cells in patients with primary / familial HLH can’t kill virus-infected or other abnormal cells in the patient’s body like they normally would. T cells and NK cells normally do this by secreting death signals into targeted abnormal cells.

The proteins made by the MUNC 13-4, STXBP2, STX11, Rab27a and LYST genes work like the machinery of a conveyor belt, and are responsible for the secretion of the death signals out of T cells and NK cells. The PRF1 gene makes a protein called perforin. It works like a key, and allows the secreted death signals to enter inside a targeted abnormal cell, where the death signals can work.

SH2D1A is responsible for a more specialized mechanism of killing, and also controls how the T cells themselves die. It is not yet entirely clear why XIAP / BIRC4 mutations cause HLH.

Treatment is very important for patients with HLH, as the condition is life-threatening. The treatments that doctors use suppress the immune system. Patients are usually treated with steroids plus chemotherapy (etoposide / VP-16) and / or an antibody therapy that destroys the T cells (called anti-thymocyte globulin or ATG). Patients may receive other medications that suppress the immune system. Additionally, your doctor may give medications that help treat any infections that are present, or that prevent new infections from occurring.

Many patients must also have their immune systems replaced by means of a bone marrow transplant in order to be cured of HLH. Your doctor can tell you if this is the case for you or your child.